Salt-sensitivity hypertension (SSHTN) is an independent predictor for cardiovascular mortality. VEGFC has been reported to be a protective role in SSHTN and hypertensive kidney injury. However, the underlying mechanisms remain largely unclear. The current study aimed to explore the protective effects and mechanisms of VEGFC against SSHTN and hypertensive nephropathy. Here, we reported that VEGFC attenuated high blood pressure as well as protected against renal inflammation and fibrosis in SSHTN mice. Moreover, VEGFC suppressed the activation of renal NLRP3 inflammasome in SSHTN mice. In vitro, we found VEGFC inhibited NLRP3 inflammasome activation, meanwhile, upregulated autophagy in high-salt-induced macrophages, while these effects were reversed by an autophagy inhibitor 3MA. Furthermore, in vivo, 3MA pretreatment weakened the protective effects of VEGFC on SSHTN and hypertensive nephropathy. Mechanistically, VEGF receptor 3 (VEGFR3) kinase domain activated AMPK by promoting the phosphorylation at Thr183 via binding to AMPK, thus enhancing autophagy activity in the context of high-salt-induced macrophages. These findings indicated that VEGFC inhibited NLRP3 inflammasome activation by promoting VEGFR3-AMPK-dependent autophagy pathway in high-salt-induced macrophages, which provided a mechanistic basis for the therapeutic target in SSHTN and hypertensive kidney injury.

Oxidative stress-associated proximal tubular cells (PTCs) damage is an important pathogenesis of hypertensive renal injury. We previously reported the protective effect of VEGFR3 in salt-sensitive hypertension. However, the specific mechanism underlying the role of VEGFR3 in kidney during the overactivation of the renin-angiotensin-aldosterone system remains unclear. In the present study, hypertensive nephropathy was established by angiotensin II (Ang II). We found that VEGFR3 was highly increased in PTCs of Ang II-infused mice. Activation of VEGFR3 mitigated renal dysfunction, pathological damage, and oxidative stress in Ang II-induced hypertensive mice. Moreover, we found that VEGFR3 restored mitophagy deficiency induced by Ang II both in vivo and in vitro to alleviate oxidative stress injury in PTCs. Furthermore, in vitro experiment demonstrated that VEGFR3 improved abnormal mitophagy by enhancing PARKIN mitochondrial translocation. LC-MS/MS and Co-IP assays identified HSPA1L as the interacted protein of VEGFR3, which promoted the mitochondrial translocation of PARKIN. Mechanistically, VEGFR3 disorder domain bound to HSPA1L, and crotonylation modification of HSPA1L at K130 by VEGFR3 was required for mitophagy regulation in the context of Ang II-induced PTCs. Finally, the protective effect of VEGFR3 on mitophagy and oxidative stress were attenuated by transfection K130 (HSPA1L-K130R) mutant plasmid in vivo and in vitro. These findings indicated that VEGFR3 alleviated oxidative stress by promoting PARKIN-dependent mitophagy pathway via regulating HSPA1L crotonylation at K130 site in Ang II-induced PTCs, which provided a mechanistic basis for the therapeutic target in hypertensive renal injury.

Cancer immunoediting is a dynamic process of tumor-immune system interaction that plays a critical role in cancer development and progression. Recent studies have highlighted the importance of innate signaling pathways possessed by both cancer cells and immune cells in this process. The STING molecule, a pivotal innate immune signaling molecule, mediates DNA-triggered immune responses in both cancer cells and immune cells, modulating the anti-tumor immune response and shaping the efficacy of immunotherapy. Emerging evidence has shown that the activation of STING signaling has dual opposing effects in cancer progression, simultaneously provoking and restricting anti-tumor immunity, and participating in every phase of cancer immunoediting, including immune elimination, equilibrium, and escape. In this review, we elucidate the roles of STING in the process of cancer immunoediting and discuss the dichotomous effects of STING agonists in the cancer immunotherapy response or resistance. A profound understanding of the sophisticated roles of STING signaling pathway in cancer immunoediting would potentially inspire the development of novel cancer therapeutic approaches and overcome the undesirable protumor effects of STING activation.

ABSTRACT Young and middle‐aged adults with hypertension develop the disease earlier and accrue longer exposure to elevated blood pressure, conferring higher lifetime cardiovascular risk. However, reliable markers predicting long‐term major adverse cardiovascular events (MACEs) in this group remain unclear. Insulin resistance (IR) is crucial to hypertensive pathophysiology, but direct measurement is impractical. We evaluated the prognostic value of three laboratory‐derived IR indices, the triglyceride—glucose (TyG) index, the triglyceride (TG) to high‐density lipoprotein cholesterol (HDL‐C) ratio (TG/HDL‐C), and the metabolic score for IR (METS‐IR), in predicting MACEs. In this retrospective cohort of 4861 patients aged 18–65 years with primary hypertension, baseline indices were calculated and classified into tertiles. Patients were followed for a median of 73 months, during which 372 MACEs occurred. Multivariable Cox regression showed that higher TyG, TG/HDL‐C, and METS‐IR were independently associated with increased MACEs risk. In fully adjusted models, each standard deviation increase in METS‐IR conferred a 55.7% higher risk (HR = 1.557, 95% CI: 1.154–2.101, p < 0.01), and patients in the highest tertile had more than double the risk vs. the lowest. METS‐IR showed superior discrimination (AUC = 0.803, 95% CI: 0.774–0.886) and significant net reclassification improvement (NRI = 0.147, 95% CI: 0.073–0.239, p = 0.001) and integrated discrimination improvement (IDI = 0.006, 95% CI: 0.002–0.010, p = 0.002), whereas TyG showed borderline benefit and TG/HDL‐C offered no incremental value. These findings highlight METS‐IR as a pragmatic predictor of long‐term cardiovascular risk in younger hypertensive patients, supporting its integration into clinical risk stratification.

Background:Endothelial dysfunction, characterized by impaired flow-mediated vasodilation (FMD), is associated with atherosclerosis. However, the relationship between FMD, plaque morphology, and clinical outcomes in patients with acute coronary syndrome (ACS) remains underexplored. This study aims to investigate the influence of FMD on the morphology of culprit plaques and subsequent clinical outcomes in patients with ACS. Methods:This study enrolled 426 of 2482 patients who presented with ACS and subsequently underwent both preintervention FMD and optical coherence tomography (OCT) between May 2020 and July 2022. Impaired FMD was defined as an FMD% less than 7.0%. Major adverse cardiac events (MACEs) included cardiac death, nonfatal myocardial infarction, revascularization, or rehospitalization for angina. Results:Within a one-year follow-up, 34 (8.0%) patients experienced MACEs. The median FMD% was 4.0 (interquartile range 2.6-7.0). Among the patients, 225 (52.8%) were diagnosed with plaque rupture (PR), 161 (37.8%) with plaque erosion (PE), and 25 (5.9%) with calcified nodules (CN). Impaired FMD was found to be associated with plaque rupture (odds ratio [OR] = 4.22, 95% confidence interval [CI]: 2.07-6.72, p = 0.012) after adjusting for potential confounding factors. Furthermore, impaired FMD was linked to an increased incidence of MACEs (hazard ratio [HR] = 3.12, 95% CI: 1.27-6.58, p = 0.039). Conclusions:Impaired FMD was observed in three quarters of ACS patients and can serve as a noninvasive predictor of plaque rupture and risk for future adverse cardiac outcomes.

Background: Coronary atherosclerosis (CAS) is a prevalent and chronic life-threatening disease. However, the detection of CAS at an early stage is difficult because of the lack of effective noninvasive diagnostic methods. The present study aimed to characterize the plasma metabolome of early-stage CAS patients to discover metabolomic biomarkers, develop a novel metabolite-based model for accurate noninvasive diagnosis of early-stage CAS, and explore the underlying metabolic mechanisms involved. Methods: A total of 100 patients with early-stage CAS and 120 age- and sex-matched control subjects were recruited from the Chinese Han population and further randomly divided into training (n = 120) and test sets (n = 100). The metabolomic profiles of the plasma samples were analyzed by an integrated untargeted liquid chromatography-mass spectrometry approach, including two separation modes and two ionization modes. Univariate and multivariate statistical analyses were employed to identify potential biomarkers and construct an early-stage CAS diagnostic model. Results: The integrated analytical method established herein improved metabolite coverage compared with single chromatographic separation and MS ionization mode. A total of 80 metabolites were identified as potential biomarkers of early-stage CAS, and these metabolites were mainly involved in glycerophospholipid, fatty acid, sphingolipid, and amino acid metabolism. An effective diagnostic model for early-stage CAS was established, incorporating 11 metabolites and achieving areas under the receiver operating characteristic curve (AUCs) of 0.984 and 0.908 in the training and test sets, respectively. Conclusions: Our study not only successfully developed an effective noninvasive diagnostic model for identifying early-stage CAS but also provided novel insights into the pathogenesis of CAS.

心律失常是急性心肌梗死的常见并发症.柯萨奇-腺病毒受体(CAR)可能通过缝隙连接蛋白等相关机制影响心梗后心律失常的发生,本文就CAR与心肌梗死后心律失常的相关性及其机制进行简要综述.

[目的]研究高位房间隔起搏(HASP)和右心耳起搏(RAAP)对心房电活动及心房结构的影响,评估HASP的安全性及临床有效性.[方法]回顾分析2013年1月—2017年1月于哈尔滨医科大学附属第二医院心内科行双腔起搏器植入的病态窦房结综合征患者142例,根据患者心房起搏电极植入的部位分为两组:HASP组100例,RAAP组42例.分别记录术前和术后P波时限、P波离散度、左心房大小及心房电极起搏参数(起搏阈值、感知、阻抗),并进行回顾性分析和对比研究.[结果]入选的142例患者的性别、年龄、既往疾病、吸烟饮酒史等因素无明显差异.RAAP组术前P波时限为(128.03±17.11)ms,术后为(144.82±21.37)ms;HASP组术前P波时限为(125.48±13.20)ms,术后为(102.08±15.23)ms;两组术后P波时限相比有统计学差异(P＜0.001).RAAP组术前P波离散度为(27.33±10.12)ms,术后为(18.64±6.59)ms;HASP组术前P波离散度为(27.12±8.58)ms,术后为(18.89±4.85)ms;两组间P波离散度虽无明显差异(P=0.47),但两组P波离散度术后较术前均减小.RAAP组与HASP组左心房内径无明显差异(34.07±5.71比32.48±4.19,P=0.10).HASP组起搏参数稳定,无额外并发症.植入起搏器1年后程控随访时发现,RAAP组患者发生心房颤动的比例为16.7％,而HASP组仅为4.0％,两组间有统计学差异(P=0.015).程控随访2年,RAAP组患者发生心房颤动的比例为28.6％,HASP组为17.0％,两组间无统计学差异.[结论]HASP是一种安全可行的起搏方式,可以明显缩短P波时限,有机会减少患者发生心房颤动的风险.

Purpose: The incidence of venous thromboembolism (VTE) in Cushing’s disease (CD) is about ten times higher than that in general population, which tends to be underestimated due to the missed detection of asymptomatic VTE events. VTE can occur at any stage of CD, mainly during the postoperative period. We aim to investigate the incidence and prothrombotic risk factors of postoperative VTE in CD patients and to further develop an assessment model to identify those at high risk of postoperative VTE events. Methods: We performed a retrospective study in 82 CD patients by evaluating their clinical, hormonal, and coagulation parameters, as well as ultrasonography and pulmonary angio-CT when necessary. Results: Nineteen patients (23.2%) developed VTE events, of which 14 developed VTE after endoscopic transsphenoidal surgery (ETS). The group of CD patients with postoperative VTE were elder (p<0.001), had more infection (p<0.05) and reduced mobility (p<0.05), higher HbA1c, and more severe impairment of glucose tolerance than those without. By using stepwise regression analysis, we obtained 4 independent risk factors for postoperative VTE: age, 2-h insulin in OGTT, current infection, and postoperative bedtime. Then a VTE risk assessment nomogram model was established to predict the patients at high risk of VTE. In this nomogram model, 70 patients (85.7%) were classi�ed correctly, and area under the curve was 0.899 (95%CI, 0.787-0.999). Conclusion: Advanced perioperative assessment needs to be taken to screen those with high VTE risks in CD patients. Moreover, physical movement and antithrombotic prophylaxis seems to be warranted during perioperative period.

Cancer is a disease with high morbidity and mortality in the world. In the past, the main treatment methods for cancer patients were surgery, radiotherapy and chemotherapy. However, with early treatment, the recurrence rate of cancer is higher, and the drug resistance of cancer cells is faster. In recent years, with the discovery of immune escape mechanism of cancer cells, Immunotherapy, especially Immune Checkpoint Inhibitors (ICIs), has made a breakthrough in the treatment of solid tumors, significantly prolonging the overall survival time and disease-free progression in some solid tumors, and its clinical benefits are more prominent than those of traditional anti-tumor drugs, which has become the hope of cancer patients after the failure of multi-line therapy. More and more studies have shown that there is a correlation between cancer driving genes and the clinical benefits of ICIs treatment, and the therapeutic effects and adverse reactions of ICIs can be predicted by the status of driving genes. Therefore, screening potential biomarkers of people who may benefit from immunotherapy in order to maximize the therapeutic benefits is a top priority. This review systematically summarizes the cancer driving genes that may affect the clinical benefits of immune checkpoint inhibitors, and provides accurate scientific basis for clinical practice.

ObjectiveImmune checkpoint inhibitors (ICIs) have changed the outcomes of a variety of cancers in an unprecedented manner. Gut microbiome plays a crucial regulatory role in the antineoplastic therapy of ICIs, which can be influenced by antibiotic (ABX) administration. In this efficacy evaluation, we aimed to clarify the correlations of ABX administration with the survival of cancer patients receiving ICIs treatment.MethodThe eligible literatures were searched using PubMed, Cochrane Library, Web of Science, and Clinical trials.gov databases before Nov 2021. The correlations of ABX administration with progression-free survival (PFS) and overall survival (OS) were determined using Hazard ratios (HRs) coupled with 95% confidence intervals (CIs).ResultsA total of 12 studies enrolling 6010 cancer patients receiving ICIs treatment were included in this efficacy evaluation. ABX administration was significantly correlated worse PFS (HR=1.60, 95%CI=1.33-1.92, P<0.00001) and OS (HR=1.46, 95%CI=1.32-1.61, P<0.00001). Similar results were found in the subgroup analysis of non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC) and melanoma.ConclusionsABX use during ICIs treatment of cancer may significantly shorten PFS and OS. ABX should be used cautiously in cancer patients receiving ICIs. However, further validations are still essential due to existing publication bias.

Objectives This study aimed to compare the effect of atorvastatin 60 (AT60) mg to that of rosuvastatin 10 (RT10) mg on the morphological changes in lipid-rich plaques (LRPs) and plaque volume, using serial optical coherence tomography (OCT) and intravascular ultrasound imaging (IVUS). Background Intensive lipid lowering therapy by statin provides more clinical benefit compared to that of moderate lipid lowering therapy. Methods Fifty patients who underwent OCT and IVUS at baseline, 6, and 12 months were grouped by statin therapy into the AT60 mg (n = 27) and RT10 mg (n = 23) groups. The relationships between absolute and percentage changes in biomarkers and fibrous cap thickness (FCT) during follow-up were investigated using a simple regression analysis. Results At 6 months, the mean low-density lipoprotein cholesterol level reduced from 113.5 to 65.5 mg/dl (AT60 mg group) and 100.2 to 72.2 mg/dl (RT10 mg groups). A continuous increase in FCT from baseline to 12 months was observed in both groups (p < .001, p < .001, respectively). Mean lipid arc significantly decreased in both AT60 mg (189.0 +/- 55.9 degrees, 170.9 +/- 60.2 degrees, 155.6 +/- 50.6 degrees, p < .001) and RT10 mg (160.0 +/- 45.6 degrees, 151.2 +/- 48.5 degrees, 141.1 +/- 52.9 degrees, p = .010) groups. Plaque burden did not change significantly in both groups. Conclusions Lipid-lowering therapy effect with AT60 mg was equivalent to that of RT10 mg in terms of change in plaque morphology. AT60 mg showed more intensive low-density lipid cholesterol level reduction compared to RT10 mg while RT10 mg was effective in increasing the high-density lipid cholesterol level. Both statin therapies could effectively stabilize LRPs.

With the development of anti-tumor drugs, tyrosine kinase inhibitors (TKIs) are an indispensable part of targeted therapy. They can be superior to traditional chemotherapeutic drugs in selectivity, safety, and efficacy. However, they have been found to be associated with serious adverse effects in use, such as myocardial infarction, fluid retention, hypertension, and rash. Although TKIs induced arrhythmia with a lower incidence than other cardiovascular diseases, much clinical evidence indicated that adequate attention and management should be provided to patients. This review focuses on QT interval prolongation and atrial fibrillation (AF) which are conveniently monitored in clinical practice. We collected data about TKIs, and analyzed the molecule mechanism, discussed the actual clinical evidence and drug-drug interaction, and provided countermeasures to QT interval prolongation and AF. We also pooled data to show that both QT prolongation and AF are related to their multi-target effects. Furthermore, more than 30 TKIs were approved by the FDA, but most of the novel drugs had a small sample size in the preclinical trial and risk/benefit assessments were not perfect, which led to a suspension after listing, like nilotinib. Similarly, vandetanib exhibits the most significant QT prolongation and ibrutinib exhibits the highest incidence in AF, but does not receive enough attention during treatment.

Radiation therapy for cancer can lead to off-target toxicity and can be ineffective against refractory differentiated thyroid cancer. The nanoscale metal organic frameworks (NMOFs) have shown great potential in cancer diagnostic and treatment due to their advantages in the aspect of structural diversities, high intrinsic biodegradability and drug-loading capacities. Here, we provide that intratumoral injection, in mouse of refractory differentiated thyroid cancer.In this work, we used the therapeutic 131I radioisotope modified Zr-MOF (Zr-MOF@131I) with aim to enable long-term relief of tumour therapy, which has successfully eliminated tumour at ralatively low radioactivity doses. Polyethylene glycol (PEG) was coated into Zr-MOF and, as a result, circulation time was significantly improved by intratumoral injection. These findings therefore suggest that nanoparticles could be used in vivo combined therapy. On injection, while it is a highly effective drug for radioisotope, Zr-MOF with attenuation ability could apply for a radio-sensitizer to enhance inner radiotherapy (RT). The local therapy, which uses only biocompatible components, might enable new strategies for local tumour treatments. These could be further combined with systemic therapeutic responses for the inhibition of refractory differentiated thyroid cancer and the prevention of tumour recurrence in patients.

Introduction: The complex electrophysiological phenomena related to the atrioventricular node (AVN) are due to its complex anatomical structures. Aside from the inferior nodal extension (INE), other node-like tissues, such as the retroaortic node (RN), have been less described and may also share the mechanism of normal conduction and abnormal conduction in AVN re-entrant tachycardia (AVNRT). Methods: High-density sections of the entire AVN were obtained from rats and rabbits. Fibrosis was analyzed by Masson’s trichrome staining. Connexin (Cx43, Cx40, and Cx45) and ion channel (Nav1.5, Cav3.1, and HCN4) proteins were immunohistochemically labeled for the analysis of tissue features. Three-dimensional (3D) reconstruction of the AV junction was performed to clarify the relationships among different structures. Results: The RN expressed the same connexin isoforms as the compact node (CN) and INE. Nav1.5 labeling was present at a low level in the CN, RN and INE, where Cav3.1 and HCN4 were expressed. The CN connected with the RN in a narrow strip pattern at the level of the start of the CN. The RN presented as a shuttle shape and was the only tissue directly connected with the atrium in the anterior septum. Conclusion: The RN connects with the AVN anatomically, suggesting that there is direct electrical conduction between them. The entrance of the atria into the AVN is the distal part of the RN, which may form the fast pathway of the AVN.

目的 研究急性心肌梗死后房室传导阻滞(AVB)大鼠房室结区柯萨奇病毒-腺病毒受体(CAR)和缝隙连接蛋白(Cx)45定位和表达情况,了解缺血相关AVB的发生机制及房室结区的电生理特征.方法 选择SD大鼠,随机分为模型组(n=12)和假手术(SH)组(n=6).模型组根据AVB持续时间不同分为AVB 2 h组(n=6)和AVB 4 h组(n=6).结扎大鼠右冠状动脉建立AVB模型,分别于建模后2h和4h对模型组和SH组取材.对房室结区行连续切片,行免疫荧光标记检测CAR和Cx45的定位及表达情况.行Western blot定量分析各组房室结区CAR和Cx45蛋白的表达情况.结果 免疫荧光标记显示CAR和Cx45主要定位于房室结,模型组(AVB 2h和AVB 4h组)与SH组相比,CAR和Cx45表达增加.Western blot显示AVB 2 h组CAR和Cx45表达增加,与SH组相比,蛋白表达差异有统计学意义(P＜0.05);AVB 4 h组相比于SH组蛋白表达增多,但无统计学意义;CAR和Cx45蛋白表达相关性分析显示,CAR和Cx45的表达具有明显正相关(r=0.7030,P＜0.05).结论 急性心肌梗死后AVB早期大鼠房室结区CAR和Cx45表达增加,且CAR和Cx45的表达呈正相关.

近年来对射血分数保留的心力衰竭(HFpEF)的理解已经从舒张功能障碍转变为一系列导致左心室充盈压力升高和运动不耐受的生理损伤,故防治的重点已转向生活方式相关因素.最近的研究表明,肥胖是预防和管理HFpEF患者潜在可改变的目标之一.本综述讨论了新出现的流行病学、机制和临床证据,还总结了发展运动训练和减肥作为管理HFpEF的有效治疗策略的现有证据和不足.

心脏性猝死(SCD)占心肌梗死(MI)后死亡率的50％.大多数SCD是由于室性快速性心律失常引发心脏骤停等多个机制造成的.尽管目前针对MI的治疗已经足够成熟,但MI后患者SCD的几率依旧很高,本文就MI后SCD的风险分层手段作一综述,以便于预防.